Colchicine drug-to-drug interactions

ABSTRACT

The use of oral colchicine solutions in combination with other therapeutics, while minimizing toxic drug to drug interactions are described herein. Related compositions are also provided.

RELATED APPLICATIONS

This Application is a Continuation of U.S. application Ser. No.15/848,498, filed Dec. 20, 2017, entitled “COLCHICINE DRUG-TO-DRUGINTERACTIONS”. The entire contents of this application is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

Colchicine is an alkaloid compound found in plant extracts that is usedto treat diseases such as gout, familial Mediterranean fever (FMF),pericarditis, Behçet's disease, atrial fibrillation, amyloidosis,calcium pyrophosphate deposition disease (pseudogout), cirrhosis of theliver, sarcoid arthritis, and inflammatory diseases.

Colchicine has been marketed for decades as a solid oral dosage form,such as a tablet administered to patients once or twice a day.Single-ingredient colchicine tablets (0.6 mg dosage strength) wereavailable in the United States for decades as marketed but unapprovedproducts. The first FDA approved single-ingredient oral colchicineproduct was Mutual Pharmaceutical's colchicine 0.6 mg tablets (Colcrys®,NDA 022352), which was approved in July 2009 for treatment of familialMediterranean Fever, and treatment of acute flares of gout; approval forthe prophylactic treatment of gout was granted in October 2009.Mitigare® (colchicine) Capsules (NDA 024820) was also approved for theprophylactic treatment of gout in 2014 based on the FDA finding ofsafety and efficacy for the probenecid-colchicine combination product.

SUMMARY OF THE INVENTION

The invention in some aspects is a pharmaceutical solution or suspensionsuitable for oral administration comprising colchicine and apharmaceutically acceptable solvent system in combination with one ormore other drugs.

In some aspects the invention is a method of treating a colchicinesensitive disorder, by orally co-administering a liquid colchicinesolution and a P-gp inhibitor to a human subject having a colchicinesensitive disorder in an effective amount to treat the disorder.

In some embodiments the P-gp inhibitor is carvedilol phosphate. In someembodiments the dose of colchicine is 0.5-1.2 mg/dose/day. In someembodiments the dose of carvedilol phosphate is 10-80 mg/dose/day. Inother embodiments there is no significant effect on colchicine bloodlevels when the liquid colchicine solution is taken in conjunction withcarvedilol phosphate. In some embodiments after administration of a 0.6mg (0.12 mg/mL, 5 mL) liquid colchicine solution to human subjects, witha multiple oral doses of carvedilol phosphate extended-release capsule,40 mg the Cmax of colchicine is substantially similar to the Cmax ofcolchicine administered alone under the same conditions. In yet otherembodiments after administration of a 0.6 mg (0.12 mg/mL, 5 mL) liquidcolchicine solution to human subjects, with oral doses of carvedilolphosphate extended-release capsule, 40 mg the 90% CIs for Cmax,AUC_(0-last) and AUC_(0-inf) are contained within the 80.00 to 125.00%limits.

In other aspects the invention is a method of treating a colchicinesensitive disorder, by orally co-administering a liquid colchicinesolution and a CYP3A4 inhibitor to a human subject having a colchicinesensitive disorder in an effective amount to treat the disorder.

In some embodiments the CYP3A4 inhibitor is a strong CYP3A4 inhibitor,such as posaconazole. In some embodiments the dose of posaconazole is300-600 mg/dose/day. In other embodiments the dose liquid colchicinesolution is reduced to 2 mL/day when coadministered with posaconazole.In some embodiments there is a 3 fold increase in colchicine bloodlevels when posaconazole is co-administered with liquid colchicinesolution.

In some embodiments after administration of a 0.6 mg (0.12 mg/mL, 5 mL)liquid colchicine solution to human subjects, with oral doses ofposaconazole the C_(max) of colchicine is significantly higher than theC_(max) of colchicine administered alone under the same conditions. Inyet other embodiments after administration of a 0.6 mg (0.12 mg/mL, 5mL) liquid colchicine solution to human subjects, with posaconazole the90% CI's for C_(max) and AUC_(0-last) fell outside the 80 to 125%boundaries for bioequivalence. In some embodiments mean colchicineC_(max) values are elevated by at least 2 fold from approximately 2.0ng/mL (alone) to approximately 4.7 ng/mL (with posaconazole).

In some embodiments the CYP3A4 inhibitor is a weak CYP3A4 inhibitor,such as amlodipine besylate. In other embodiments the dose of amlodipinebesylate is 5-10 mg/dose/day. In some embodiments there is nosignificant effect on colchicine blood levels when liquid colchicinesolution is taken in conjunction with amlodipine besylate.

In some embodiments after administration of a 0.6 mg (0.12 mg/mL, 5 mL)liquid colchicine solution to human subjects, with amlodipine besylatethe C_(max) of colchicine is slightly higher than the C_(max) ofcolchicine administered alone under the same conditions. In yet otherembodiments after administration of a 0.6 mg (0.12 mg/mL, 5 mL) liquidcolchicine solution to human subjects, with amlodipine besylate theupper 90% CI's for C_(max), AUC_(0 last) and AUC_(0-inf) fell outsidethe 80 to 125% boundaries for bioequivalence.

In some embodiments the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor,such as ciprofloxacin hydrochloride. In some embodiments the dose ofciprofloxacin hydrochloride is 20-750 mg/dose/day. In some embodimentsthere is no significant effect on colchicine blood levels when liquidcolchicine solution is taken in conjunction with ciprofloxacinhydrochloride. In some embodiments the dose of colchicine is 0.5-1.2mg/dose/day.

In some embodiments after administration of a 0.6 mg (0.12 mg/mL, 5 mL)liquid colchicine solution to human subjects, with a ciprofloxacinhydrochloride the C_(max) of colchicine is substantially similar to theC_(max) of colchicine administered alone under the same conditions. Inyet other embodiments after administration of a 0.6 mg (0.12 mg/mL, 5mL) liquid colchicine solution to human subjects, with ciprofloxacinhydrochloride the 90% CIs for C_(max), AUC_(0-last) and AUC_(0-inf) arecontained within the 80.00 to 125.00% limits.

The invention in some aspects is a method of treating a colchicinesensitive disorder, by orally administering a liquid colchicine solutionto a human subject having a colchicine sensitive disorder in aneffective amount to treat the disorder, wherein the safety profile forthe liquid colchicine solution is lower than the safety profile of atablet or capsule colchicine formulation that is administered to a humansubject having a colchicine sensitive disorder. In some embodiments thebioavailability is similar between the liquid colchicine solution andthe tablet or capsule colchicine formulation, based on a Caco2 study. Insome embodiments the safety profile is measured in terms of adverseevents and wherein the liquid colchicine solution results in feweradverse events than the tablet or capsule colchicine formulation. Insome embodiments the colchicine sensitive disorder is selected fromgout, prophylactic treatment of gout, familial Mediterranean fever(FMF), prophylactic treatment of FMF, pericarditis, prophylactictreatment of pericarditis, Behçet's disease, atrial fibrillation,prophylactic treatment of atrial fibrillation, amyloidosis, calciumpyrophosphate deposition disease (pseudogout), cirrhosis of the liver,sarcoid arthritis, inflammatory diseases, and disc diseases and relatedspinal disorders.

In other embodiments the methods further comprise a step of monitoringthe subject for colchicine adverse events.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention. This invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description or illustrated in the drawings. The inventionis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, the phraseology and terminology usedherein is for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

BRIEF DESCRIPTION OF DRAWINGS

The figures are illustrative only and are not required for enablement ofthe invention disclosed herein.

FIG. 1 is a graph depicting a determination of mean (SD) colchicineplasma concentrations (ng/mL) vs. time (Semi-log Scale)—PK Population inhuman clinical study 1 (Example 1).

FIG. 2 is a graph depicting a determination of mean (SD) colchicineplasma concentrations (ng/mL) vs. time (Semi-log Scale)—PK Population inhuman clinical study 2 (Example 2).

FIG. 3 is a graph depicting a determination of mean (SD) colchicineplasma concentrations (ng/mL) vs. time (Semi-log Scale)—PK Population inhuman clinical study 3 cohort 1 (Example 3).

FIG. 4 is a graph depicting a determination of mean (SD) colchicineplasma concentrations (ng/mL) vs. time (Semi-log Scale)—PK Population inhuman clinical study 3 cohort 2 (Example 3).

FIG. 5 is a graph depicting a determination of mean (SD) colchicineplasma concentrations (ng/mL) vs. time (Semi-log Scale)—PK Population inhuman clinical study 3 cohort 3 (Example 3).

DETAILED DESCRIPTION

Colchicine is administered to patients as a solid oral dosage form, suchas a tablet or capsule. The development of liquid oral solutions ofcolchicine have not progressed because of the instability of thecolchicine in a liquid formulation. Solutions having reasonable shelflife have not been developed. For instance, an article published in DrugDevelopment and Industrial Pharmacy, 15(11), 1905-1909 (1989) by Habib,et. al., investigated the stability of colchicine and showed that thereis photodegradation of colchicine in solution, especially in thepresence of glycerin. Other additives, such as lithium carbonate,p-aminobenzoic acid, and uric acid, used in this study did not preventthe degradation of the colchicine, and furthermore, are not acceptableexcipients for an oral solution.

It was discovered quite surprisingly that liquid solutions of colchicinefor oral administration are stable at ambient temperature and havestable pH for extended periods of time. It was also discovered that oralsolutions caused significantly fewer adverse events in human patientsrelative to tablets or capsules. Even with the fewer adverse events,these solutions result in similar blood levels of colchicine in patientsto those produced by tablets and capsules.

Thus, the invention encompasses liquid formulations of colchicine, alsoreferred to herein as colchicine oral solutions. The colchicine oralsolutions have enhanced properties such as fewer adverse events,enhanced stability sufficient for significant shelf life and improvedproperties when used in combination with other drugs. Adverse events, asused herein, refers to any undesirable experience associated with theuse of one or more medical products in a patient which is associatedwith the use and/or testing of the medical product, and may also bereferred to herein as toxicity.

Applicant has conducted several human clinical trials on the liquidcolchicine solution and has demonstrated that the solution has severaladvantages over the tablet or capsule formulations of colchicine. Asshown in the Examples below, Applicant has conducted clinical trials onhumans, including a comparative bioavailability study, including afood-effect arm, and multiple drug-drug interaction (DDI) studies[including studies with a P-gp inhibitor and three CYP3A4 inhibitors(strong, moderate and weak)]. Applicant has also demonstrated comparablepermeability and/or bioavailability of the Colchicine Oral Solution(i.e. liquid colchicine solution of the invention) vs. marketedcolchicine products (tablets and capsules) in an in vitro Caco-2 study.Applicant has also demonstrated comparable bioavailability and feweradverse events in in vivo human clinical studies with the ColchicineOral Solution when compared to published studies of marketed colchicinetablets and capsules.

Although it was found that the liquid solutions have comparablepermeability and bioavailability, it was found quite surprisingly, thatwhen liquid colchicine formulations are co-administered with severaldrugs which normally cause drug to drug interactions with colchicine,the combinations have been demonstrated to be within safety limits forco-administration.

Drug to drug interactions occur when multiple drugs are administeredsimultaneously or at staggered administration times and can affect theactivity of one or both of the drugs. Interaction between the drugs inquestion is classified as pharmacodynamics drug interaction, wherebythere is a change in sensitivity, etc., to the drug at its site ofaction, and pharmacokinetic drug interaction, where there is a change inthe in vivo kinetics of the drug. With respect to the latter,clinically, the in vivo kinetics of a drug is still unknown and evenwhen it is known, unexpected results occur when drugs are combined.Pharmacokinetic drug interaction sometimes develop because the drugsthemselves compete for one route (enzymes, carriers, etc.) when drugsthat use the same routes in terms of drugs absorption, distribution,metabolism or excretion are used concomitantly.

Information on drug interactions with colchicine has beenwell-established in the decades the active ingredient has been used inFDA-approved products. There are numerous studies and references thatadvise physicians to monitor patients on colchicine when takenconcomitantly with drugs that interact with CYP3A4 and/or P-glycoprotein(P-gp).

Since colchicine is metabolized by cytochrome P450 (CYP) 3A4demethylation in the liver, it may interact with substrates of thisenzyme system, including estrogen, steroids, dapsone, diltiazem,erythromycin, lidocaine, lovastatin (and most other statins), midazolam,quinidine, terfenadine, testosterone, nifedipine, and verapamil. It mayalso be affected by inhibitors of this enzyme system, such as diltiazem,gestodene, grapefruit juice, ketoconazole, toleadomycin, anderythromycin.

P-glycoprotein modulators or substrates that may interact withcolchicine include morphine, doxorubicin, vinblastine, vincristine,paclitaxel, digoxin, quinidine, amprenavir, indinavir, nelfinavir,ritonavir, saquinavir, loperamide, josamycin, erythromycin,clarithromycin, cyclosporine, aldosterone, dexamethasone, prednisolone,progesterone, verapamil, talinolol, fexofenadine, cimetidine,amitriptyline, nortriptyline, phenytoin, and simvastatin.

Administration of colchicine with macrolide antibiotics such asclarithromycin has been shown to impair colchicine elimination,resulting in excess drug accumulation. Acute myopathy has been reportedwhen colchicine is used with pravastatin. Rhabdomylosis has beenreported when colchicine was used with atorvastatin.

In order to determine whether colchicine oral solution had similar drugto drug interactions with drugs competing for the same pathways ascolchicine delivered in tablets and capsules, several drug interactionsstudies were conducted with colchicine oral solution. Because colchicineis a substrate of the CYP3A4 metabolizing enzyme and the effluxtransporter P-gp, the pharmacokinetics of Colchicine Oral Solution wereevaluated following administration with posaconazole (a strong CYP3A4inhibitor), ciprofloxacin hydrochloride (a moderate CYP3A4 inhibitor),amlodipine besylate (a weak CYP3A4 inhibitor) and carvedilol phosphate(a P-gp inhibitor). None of these drugs has been administered togetherwith colchicine in any type of formulation to examine drug to druginteractions in scientifically valid/credible studies prior to theinvention. Prior to the data generated according to the invention it wasnot predictable how these drugs would affect one another.

Colchicine oral solution was well-tolerated in the first study whenadministered as a single oral 0.6-mg dose alone and in combination withmultiple doses of Coreg CR® (carvedilol phosphate) Extended-ReleaseCapsules (P-gp inhibitor). Given that colchicine is a known substratefor P-gp, it was hypothesized that an inhibitor of P-gp such ascarvedilol phosphate could potentially affect the PK profile ofcolchicine. In this study, it was surprisingly demonstrated thatcarvedilol phosphate had no effect on the C_(max) of colchicine. Thepercent GMR of AUC_(0-last) (co-administration with carvedilolphosphate/colchicine alone) was 117.9% and its 90% CI was in the rangeof 112.0%-124.1%. The 90% CIs for C_(max), AUC_(0-last) and AUC_(0-inf)were contained within the 80 to 125% boundaries. The results suggestthat colchicine oral solution can be used together with carvedilolphosphate at usual single drug doses, without adjustments.

Similar to the study with carvedilol phosphate, colchicine oral solutionwas well tolerated in the study with CYP3A4 inhibitors when administeredas a single, oral, 0.6-mg dose alone and in combination. Colchicine oralsolution was administered with multiple doses of posaconazole (strongCYP3A4 inhibitor), ciprofloxacin hydrochloride (moderate CYP3A4inhibitor) and amlodipine besylate (weak CYP3A4 inhibitor).Ciprofloxacin hydrochloride (moderate CYP3A4 inhibitor) and amlodipinebesylate (weak CYP3A4 inhibitor) had only minimal effects on the C_(max)of colchicine. The effect was clinically small and dose adjustment forcolchicine is not necessary when colchicine is co-administered with theamlodipine besylate or ciprofloxacin hydrochloride.

However, the combination of colchicine+posaconazole (strong CYP3A4inhibitor) resulted in a surprisingly high increase in colchicine bloodlevels-greater than 3 fold increase. This increase was unexpected assome previously reported studies with other strong CYP3A4 inhibitorsco-administered with solid dosage forms of colchicine did not show thisincrease. Furthermore this drug interaction has never been demonstratedwith a colchicine oral liquid formulation. As result the dose of thedrugs should be adjusted when colchicine+posaconazole are administeredtogether.

Colchicine plasma levels were markedly elevated when colchicine oralsolution was administered with a strong CYP3A4 inhibitor (i.e.,posaconazole). There were no significant effects when colchicine oralsolution was coadministered with a moderate CYP3A inhibitor (i.e.,ciprofloxacin hydrochloride) a weak CYP3A inhibitor (i.e., amlodipinebesylate) or a P-gp inhibitor (i.e., carvedilol phosphate).

In addition to the drug to drug interactions, colchicine is known to bea relatively toxic drug. It was discovered herein that colchicine causedfewer adverse events when delivered as a liquid solution than as atablet or capsule. The data from the bioavailability studies describedherein showed that the administration of liquid oral colchicine wasassociated with only 0.1% adverse events/study subject. In contrast tothis, published studies have shown that Mitigare® (colchicine) Capsulesare associated with 1.19% adverse events/study subject and Colcrys®tablets are associated with 0.33% adverse events/study subject.

Additionally, when colchicine oral solution was administered incombination with CYP (strong, moderate and weak) or P-gp inhibitors inthe DDI studies, quite surprisingly, the incidence of TEAEs did notincrease and there were no treatment related discontinuations. Therewere no statistically significant or clinically meaningful changes frombaseline in hematology, clinical chemistry, vitals, ECG or urineanalysis seen in any of studies, no serious adverse events (SAEs) werereported.

Thus, in some embodiments the drug product is a ready-to-use colchicinesolution for oral administration. The formulation may contain 0.01-1.0mg/mL of colchicine. For a 0.12 mg/mL formulation, the recommended doseis 5 mL to deliver a once or twice daily (maximum dose of 1.2 mg/day forsome indications such as gout).

Colchicine,N-((7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo(a)heptalen-7-yl)-acetamide(CAS No. 64-86-8), is a pale yellow powder soluble in water in 1:25dilution, having a pH in solution of 5.9 and a pK of 12.35 at 20° C.Colchicine is an alkaloid found in extracts of certain plants such asColchicum autumnale and Gloriosa superba. Colchicine arrests celldivision in animals and plants. It has adversely affectedspermatogenesis in humans and in some animal species under certainconditions.

As used herein, “colchicine” refers to colchicine base, its salt, orsolvate or derivative or isomer or polymorph thereof. Suitable compoundsinclude the free base, the organic or inorganic salts, isomers, isomersalts, solvates, polymorphs, complexes, etc. Colchicine has thefollowing structure:

Also provided herein are methods of treating gout, familialMediterranean fever (FMF), Behçet's disease, cardiovascular disease(atrial fibrillation, pericarditis), amyloidosis, calcium pyrophosphatedeposition disease (pseudogout), cirrhosis of the liver, sarcoidarthritis, inflammatory diseases, and Disc diseases & related spinaldisorders comprising administering to a patient, such as a child or anelderly patient, an oral liquid formulation comprising colchicine asdescribed herein. In some embodiments, oral liquid formulationsdisclosed herein can also be used to treat for other conditions (e.g.,skin conditions) known in the art (Ben-Chetrit E, Levy M. Colchicine:1998 update. Semin Arthritis Rheum. 1998; Yurdakul S, Mat C, Tüzün Y,Ozyazgan Y, Hamuryudan V, Uysal O, Senocak M, Yazici H. A double-blindtrial of colchicine in Behçet's syndrome. Arthritis Rheum. 2001November; 44(11):2686-92. August; 28(1):48-59; Molad Y. Update oncolchicine and its mechanism of action. Curr Rheumatol Rep. 2002 June;4(3):252-6).

Commonly, geriatric populations encounter difficulty being administeredsolid oral dosage forms such as tablets and capsules. This may lead tonon-compliance with the recommended pharmacotherapy with the solid oraldosage forms and likely results in rendering the therapy ineffective.Solid oral dosage forms are usually not favorable for geriatricpopulations due to the potential risk of choking. Additionally, certainsolid oral dosage forms of medications cannot be administered simply bycrushing (e.g., patients requiring various types of feeding tubes)because of the coating or drug delivery mechanism by which the drug isreleased.

In some embodiments the oral liquid colchicine formulation is stable atroom temperature for at least 3 months, at least 6 months, at least 18months, or at least 24 months. In some embodiments the oral liquidcolchicine formulation is stable at accelerated temperatures for atleast 1 month, at least 2 months, at least 3 months, or at least 6months. In some embodiments the oral liquid colchicine formulation isdetermined to be stable when the solution has less than 5%, less than4%, less than 3%, less than 2%, less than 1% or less than 0.5% of anyone degradant. In other embodiments the oral liquid colchicineformulation is determined to be stable when the solution has less than5%, less than 4%, less than 3%, less than 2%, less than 1% or less than0.5% of total degradants. In some embodiments, degradants include βlumicolchicine, γ-lumicolchicine, colchiceine, and any other individualunknown impurities.

Currently colchicine is primarily used to treat patients suffering fromgout. An oral liquid formulation can provide physicians more flexibilityin designing dosage regimens for their patients. This is particularlyimportant since colchicine is toxic and has a narrow therapeutic index.The methods described herein are useful for the treatment of gout. Thetreatment of gout involves the prophylactic treatment of gout as well asthe treatment of acute out flares. The prophylactic treatment of goutrefers to the treatment of a patient who has had one or more goutflares, in order to reduce the occurrence of future gout flares.

Gout (or gouty arthritis) is a disease caused by a build-up of uric aciddue to an overproduction of uric acid or a reduced ability of the kidneyto get rid of uric acid. It is more common in males, postmenopausalwomen, and people with high blood pressure. Heavy alcohol use, diabetes,obesity, sickle cell anemia, and kidney disease also increase the risk.The condition may also develop in people who take drugs that interferewith uric acid excretion.

In gout, monosodium urate or uric acid crystals are deposited on thearticular cartilage of joints, tendons and surrounding tissues due toelevated concentrations of uric acid in the blood stream. This provokesan inflammatory reaction of these tissues. Gout is characterized byexcruciating, sudden, unexpected, burning pain, as well as swelling,redness, warmness, and stiffness in the affected joint. Low-grade fevermay also be present. The patient usually suffers from two sources ofpain. The crystals inside the joint cause intense pain upon action ormovement of the affected area. The inflammation of the tissues aroundthe joint also causes the skin to be swollen, tender and sore if it iseven slightly touched. Acute gouty arthritis (alternatively referred toas a gout flare or a gout attack) is a sudden attack of pain in affectedjoints, especially in the feet and legs. Chronic gout involves repeatedattacks of joint pain.

In acute gouty arthritis, symptoms develop suddenly and usually involveonly one or a few joints. The big toe, knee, or ankle joints are mostoften affected. The pain frequently starts during the night and is oftendescribed as throbbing, crushing, or excruciating. The joint appearsinfected with signs of warmth, redness, and tenderness. The attacks ofpainful joints may go away in several days, but may return from time totime. Subsequent attacks usually last longer. Some people may progressto chronic gout (chronic gouty arthritis), while others may have nofurther attacks.

If several attacks of gout occur each year, it can lead to jointdeformity and limited motion in joints. Uric acid deposits, calledtophi, develop in cartilage tissue, tendons, and soft tissues. Thesetophi usually develop only after a patient has suffered from the diseasefor many years. Deposits also can occur in the kidneys, leading tochronic kidney failure.

Colchicine can be used for treating adults with acute gouty arthritisand pain in attacks of acute gouty arthritis, and also can be usedbeneficially for treating adults with chronic gout for prophylaxis ofacute gout flares. Although its exact mode of action in the relief ofgout is not completely understood, colchicine is known to decrease theinflammatory response to urate crystal deposition by inhibitingmigration of leukocytes, to interfere with urate deposition bydecreasing lactic acid production by leukocytes, to interfere with kininformation and to diminish phagocytosis and the subsequentanti-inflammatory response. The anti-inflammatory effect of colchicineis relatively selective for acute gouty arthritis. However, other typesof arthritis occasionally respond. It is neither an analgesic nor auricosuric and will not prevent progression to chronic gouty arthritis.It does have a prophylactic, suppressive effect that helps to reduce theincidence of acute attacks and to relieve the residual pain and milddiscomfort that patients with gout occasionally experienced. In someinstances, non-steroidal anti-inflammatory drugs (NSAIDs) may also beprescribed to relieve pain and inflammation in acute gouty arthritisattacks. Strong painkillers, such as codeine, or corticosteroids mayalso be prescribed to relieve the pain.

Colchicine is rapidly absorbed from the gastrointestinal tract. Peakconcentrations occur in 0.5 to 2 hours. The drug and its metabolites aredistributed in leukocytes, kidneys, liver, spleen and the intestinaltract. Colchicine is metabolized in the liver and excreted primarily inthe feces with 10 to 20% eliminated unchanged in the urine. In someembodiments, oral liquid formulations disclosed herein are used to treatgout.

Familial Mediterranean Fever (FMF) is a recessively inherited disordercharacterized by dramatic episodes of fever, serosal inflammation andabdominal pain. This inflammatory disorder is episodic, withself-limited bouts of fever accompanied by unexplained arthritis,sterile peritonitis, pleurisy and/or skin rash. Patients often developprogressive systemic amyloidosis from the deposition of the acute phasereactant serum amyloid A (SAA). In some patients, progressive systemicamyloidosis can lead to kidney failure and death. The factors whichincite an episode are unclear. In some embodiments, colchicine can beprescribed as an anti-inflammatory therapy.

FMF is observed primarily in individuals of non-Ashkenazi Jewish,Armenian, Arab and Turkish background. Although rare in the UnitedStates, incidence of FMF in Middle Eastern populations can be as high as1:7 in Armenian populations and 1:5 in non-Ashkenazi Jewish populations.

FMF attacks are characterized by a massive influx of polymorphonuclearleukocytes (PMNs) into the affected anatomic compartment. At thebiochemical level, patients have been reported to have abnormal levelsof C5a inhibitor (Matzner and Brzezinski, “C5a-inhibitor deficiency inperitoneal fluids from patients with familial Mediterranean fever,” N.Engl. J. Med., 311:287-290 (1984)), neutrophil-stimulatory dihydroxyfatty acids (Aisen et al, “Circulating hydroxy fatty acids in familialMediterranean fever,” Proc. Natl. Acad. Sci. USA, 2:1232-1236 (1985)),and dopamine O-hydroxylase (Barakat et al, “Plasma dopaminebeta-hyroxylase: rapid diagnostic test for recurrent hereditarypolyserositis,” Lancet, 2:1280-1283 (1988)). Although linkage studieshave placed the gene causing FMF (designated MEFV) on chromosome 16p(Pras et al., “Mapping of a gene causing familial Mediterranean fever tothe short arm of chromosome 16,” N. Engl. J. Med., 326:1509-1513 (1992);Shohat et al., “The gene for familial Mediterranean fever in bothArmenians and non-Ashkenazi Jews is linked to the α-globin complex on16p: evidence for locus homogeneity,” Am. J. Hum. Genet., 51:1349-1354(1992); Pras et al, “The gene causing familial Mediterranean fever mapsto the short arm of chromosome 16 in Druze and Moslem Arab families,”Hum. Genet., 94:576-577(1994); French FMF Consortium, “Localization ofthe familial Mediterranean fever gene (FMF) to a 250 kb-interval innon-Ashkenazi Jewish founder haplotypes,” Am. J. Hum. Genet.,59:603-612(1996)), the genetic basis of FMF has not previously beenidentified. In some embodiments, oral liquid formulations disclosedherein are used to treat FMF.

Behcet's disease is a chronic multisystem disease characterized by oraland genital aphthae, arthritis, cutaneous lesions, and ocular,gastrointestinal, and neurologic manifestations. It was first describedby the Turkish dermatologist Hulusi Behcet in 1937 as “recurrent oralaphthous ulcers, genital ulcers, and ‘hypopyon-uveitis.’” The diagnosisof Behcet's disease is based on clinical criteria as established byO'Duffy and Goldstein and the International Study Group. Complexaphthosis is the presence of almost constant, multiple oral or oral andgenital aphthae in the absence of systemic manifestations. Thesepatients must be distinguished from those with Behcet's disease.Colchicine has been used as a treatment for Behcet's disease through itsability to inhibit of neutrophil functions (Hirohata et al., Behçet'sdisease. Arthritis Res Ther 2003 5:139 DOI: 10.1186/ar757). In someembodiments, oral liquid formulations disclosed herein are used to treatBehçet's Disease.

The prevalence of Behcet's disease is higher in the Middle East andJapan where it is approximately 1 in 1000. The disease is far lesscommon in northern Europe, the United States, and the United Kingdom.The mean age of onset ranges from the mid to late 20s to the fourthdecade, according to several series, with a slightly higher male tofemale ratio. It is relatively rare in children and the elderly.Behcet's disease is also uncommon among black Africans who, when theyare affected, tend to have more mucocutaneous features. Although adefinitive pattern of inheritance has not been elucidated, familialcases have been reported. Patients with complex aphthosis are probably asubset of patients with recurrent aphthous stomatitis, which is definedas the recurrence of 1 or more painful oral ulcers at intervals rangingfrom days to months. The prevalence of recurrent aphthosis ranges from5% to 66%. Onset may occur in childhood or adolescence and some patientsexperience a decrease in frequency with advancing age. (source: J. VGhate and J. L. Jorizzo, “Behcet's disease and complex aphthosis”,Journal of the American Academy of Dermatology, 1999, 40(1), 1-18.)

Cardiovascular disease (CVD) involves the heart of blood vessels. CVDincludes, but is not limited to coronary artery diseases (CAD), stroke,hypertensive heart disease, rheumatic heart disease, cardiomyopathy,atrial fibrillation, congenital heart disease, endocarditis,pericarditis, aortic aneurysms, peripheral artery disease, and venousthrombosis.

One very typical and dangerous arrhythmia is atrial fibrillation (AFIB).AFIB is the most common cardiac arrhythmia resulting in hospitalizationin the United States. AFIB is identified by irregular heart rhythms andis clinically defined as uncoordinated contractions of the atria.Patients often experience palpitations and have an increased risk ofstroke. Some patients may be asymptomatic. Approximately one-third ofall strokes are due to AFIB. Furthermore, the presence of AFIB makesstrokes 5-times more likely and 2-times more debilitating.

The role of colchicine in inflammation, microtubule disruption, adhesionof neutrophils, and other qualities, makes it a promising treatment forsome cardiovascular diseases (Deftereos et al., Colchicine and theHeart: pushing the envelope. J Am Coll Cardiol. 2013; 62(20):1817-1825.doi:10.1016/j.jacc.2013.08.726; Tong et al., Colchicine incardiovascular disease: an ancient drug with modern tricks. 2016 Heartdoi:10.1136/heartjnl-2015-309211). In some embodiments, oral liquidformulations disclosed herein are used to treat cardiovascular diseases(e.g., atrial fibrillation and pericarditis).

Amyloidosis is a rare and potentially fatal disease that can be eitherlocalized or systemic. There are four major types of amyloidosis. Thefour major types include immunoglobulin (primary) amyloidosis, reactive(secondary) amyloidosis, beta-2 microglobulin amyloidosis and hereditaryamyloidosis. Each different type of amyloidosis presents a differentprognosis and stems from different underlining conditions. Thepathologic features of amyloid deposits include beta-pleated sheetstructures that are composed of amyloid fibrils with diameters between 8to 10 nm. B eta-pleated sheets can be viewed under polarized light afterbeing stained using Congo Red stain, these stained fibrils display anapple green birefringence.

Secondary amyloidosis is associated with chronic inflammatory diseasessuch as FMF. The precursor protein responsible for constructing theamyloid fibrils associated with secondary amyloidosis is serum amyloidA, an acute-phase reactant. Typical sites of amyloid accumulationinclude the spleen, liver, lymph nodes, adrenal glands, and the kidneys.Symptoms that are nonspecific include complaints of weakness andfatigue. Specific complaints are directly associated to organinvolvement, these symptoms commonly include edema and pain. In someembodiments, oral liquid formulations disclosed herein are used to treatamyloidosis.

Calcium pyrophosphate deposition disease (CPDD), also known aspseudogout, chondrocalcinosis, and pyrophosphate arthropathy, is arheumatologic disorder with varied symptoms and signs arising from theaccumulation of crystals of calcium pyrophosphate dihydrate in theconnective tissues.

Pseudogout refers to the acute symptoms of joint inflammation orsynovitis: red, tender, and swollen joints that may resemble goutyarthritis. The disorder is more common in older adults. It may beasymptomatic, or it can be associated with osteoarthritis, or it canpresent as an acute or chronic inflammatory arthritis that causes painin one or more joints. The white blood cell count is often raised.

The arthritis is usually polyarticular (inflammation of several jointsin the body), although it may begin as monoarticular (one joint). CPPDcrystals tend to form within articular tissues. Knees are the mostcommonly affected joints, along with wrists and hips. In rare cases,pseudogout may affect the spinal canal and cause damage to the spinalcord. In some embodiments, oral liquid formulations disclosed herein areused to treat pseudogout.

Cirrhosis, a condition in which the liver does not function properly dueto long-term damage, typically comes on slowly over months or years.Early on, there are often no symptoms. As the disease worsens, a subjectmay become tired, weak, itchy, have swelling in the lower legs, developyellow skin, bruise easily, have fluid build-up in the abdomen, ordevelop spider-like blood vessels on the skin. The fluid build-up in theabdomen may become spontaneously infected. Other complications includehepatic encephalopathy, bleeding from dilated veins in the esophagus ordilated stomach veins, and liver cancer. Hepatic encephalopathy resultsin confusion and possibly unconsciousness. Colchicine has been shown tohave anti-fibrotic effects in relation to hepatic diseases (Leung etal., Colchicine—Update on mechanisms of action and therapeutic uses.2015. Seminar in Arthritis and Rheumatism. 45 (3), 257-67).

Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C,and non-alcoholic fatty liver disease. Typically, more than two or threedrinks per day over a number of years is required for alcoholiccirrhosis to occur. Non-alcoholic fatty liver disease is due to a numberof reasons, including being overweight, diabetes, high blood fats, andhigh blood pressure. A number of less common causes include autoimmunehepatitis, primary biliary cirrhosis, hemochromatosis, certainmedications, and gallstones. Cirrhosis is characterized by thereplacement of normal liver tissue by scar tissue. These changes lead toloss of liver function. Diagnosis is based on blood testing, medicalimaging, and liver biopsy. In some embodiments, oral liquid formulationsdisclosed herein are used to treat hepatic diseases (e.g., cirrhosis ofthe liver).

Sarcoidosis, a disease involving abnormal collections of inflammatorycells, can be involved with the joints, bones and muscles. This causes awide variety of musculoskeletal complaints that act through differentmechanisms. Approximately 5-15% of cases affect the bones, joints, ormuscles.

Sarcoid arthritis has two classifications: acute or chronic. Sarcoidosispatients with acute arthritis often also accompanies bilateral Hilarlymphadenopathy and Erythema nodosum. Usually true arthritis is notpresent, but instead periarthritis presents itself as a swelling in thesoft tissue around the joints that can be seen by ultrasonographicmethods. These joint symptoms tend to precede or occur at the same timeas erythema nodosum develops. Enthesitis also occurs in about one-thirdof patients with acute sarcoid arthritis, mainly affecting the Achillestendon and heels. Soft tissue swelling at the ankles can be prominent,and biopsy of this soft tissue reveals no granulomas, but does showpanniculitis that is similar to erythema nodosum.

Chronic sarcoid arthritis usually occurs in the setting of more diffuseorgan involvement. The ankles, knees, wrists, elbows, and hands may allbe affected in the chronic form and often in a polyarticular pattern.Dactylitis similar to that seen in Psoriatic arthritis, that isassociated with pain, swelling, overlying skin erythema, and underlyingbony changes may also occur. In some embodiments, oral liquidformulations disclosed herein are used to treat sarcoid arthritis.

Disc diseases & related spinal disorders are a group of disorders thatare quite painful. It is believed that colchicine acts directly ondiskal inflammation to reduce inflammation in the area surrounding thespinal nerve roots. Colchicine has also been shown to cause an increaseof endorphin-producing neurons in the spinal cord and to preventdeposition of amyloid in damaged disc. In some embodiments the subjecthas diskal back pain and or sciatica. In some embodiments, oral liquidformulations disclosed herein are used to treat disc diseases andrelated spinal disorders.

The liquid formulations described herein may include additionalingredients. For instance these additional components may include, butare not limited to, buffering agents, preservatives, sweeteners,flavoring agents, glycols such as propylene glycol and glycerin, asexamples, and coloring agents. Additional excipients such as tonicityagents and chelating agents are within the scope of the embodiments.

Buffering agents maintain the pH when colchicine is formulated into aliquid form. Non-limiting examples of buffering agents include, but arenot limited to, sodium bicarbonate, potassium bicarbonate, magnesiumhydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide,aluminum hydroxide/sodium bicarbonate precipitate, a mixture of an aminoacid and a buffer, a mixture of aluminum glycinate and a buffer, amixture of acid salt and an amino acid and a buffer, and a mixture of analkali salt of an amino acid and a buffer. Additional buffering agentsinclude citric acid, sodium citrate, sodium tartarate, sodium acetate,sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodiumpyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate,dibasic sodium phosphate, trisodium phosphate, tripotassium phosphate,sodium acetate, potassium metaphosphate, magnesium oxide, magnesiumcarbonate, magnesium silicate, calcium acetate, calciumglycerophosphate, calcium chloride, calcium hydroxide, calcium lactate,calcium carbonate, calcium bicarbonate, and other calcium salts. Somebuffering agents also impart effervescent qualities when a powder isincorporated into a liquid. In some embodiments, the colchicinedescribed herein, when formulated into a liquid form, comprises abuffering agent.

Preservatives include anti-microbials, anti-oxidants, and agents thatenhance sterility. Exemplary preservatives include ascorbic acid,ascorbyl palmitate, benzyl alcohol, BHA, BHT, citric acid, erythorbicacid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodiumbenzoate, sodium bisulfate, sodium metabisulfite, sodium sulfite,parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, andvanillin. In some embodiments, the colchicine described herein, whenformulated into a liquid form, comprises a preservative.

Sweeteners or sweetening agents include any compounds that provide asweet taste to make the product more palatable. This includes naturaland synthetic sugars, natural and artificial sweeteners (e.g.,sucralose), natural extracts and any material that initiates a sweetsensation in a subject. In some embodiments, the colchicine describedherein, when compounded into a liquid form, comprises a sweetener. Inother embodiments, sweeteners in liquid form are used to solvate ordissolve the colchicine described herein.

Sugars illustratively include glucose, fructose, sucrose, xylitol,tagatose, maltitol, isomaltulose, lactitol, sorbitol, mannitol,erythritol, trehalose, maltodextrin, polydextrose, and the like. Othersweeteners include glycerin, inulin, maltol, acesulfame and saltsthereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodiumcyclamate, saccharin and salts thereof, e.g., saccharin sodium orsaccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin,and the like. Sweeteners can be used in the form of crude or refinedproducts such as hydrogenated starch hydrosylates, maltitol syrup, highfructose corn syrup, and as branded proprietary blend products.Sweeteners can be used singly or combinations of two or more. Suitableconcentrations of different sweeteners can be selected based onpublished information, manufacturers' data sheets, and by routinetesting. In certain instances, an above-described flavored solutioncomponent is used to solvate or dissolves colchicine described herein.

In another embodiment, the liquid form comprises a flavoring agent orflavorant to enhance the taste or aroma of the solution component usedto solvate or dissolve the colchicine described herein. Suitable naturalor synthetic flavoring agents can be selected from standard referencebooks, such as Remington: The Science and Practice of Pharmacy (2000)and Fenaroli's Handbook of Flavor Ingredients (1994). Non-limitingexamples of suitable natural flavors, some of which can be readilysimulated with synthetic agents or combinations thereof, include almond,anise, apple, apricot, banana, blackberry, blackcurrant, blueberry,caramel, cherry, chocolate, cinnamon, cranberry, grape, lemon, lime,orange, peppermint, pineapple, raspberry, spearmint, strawberry,vanilla, etc. Also useful, particularly where the composition isintended primarily for pediatric use is tutti-frutti or bubble gumflavor, a compounded flavoring agent based on fruit flavors. Presently,preferred flavoring agents include bubble gum, strawberry, cherry,grape, orange, peppermint, and vanilla. In some embodiments, theresultant liquid form from the colchicine described herein comprises aFlavor Cherry 825.662 flavoring agent. Flavoring agents may be usedsingly or in combinations of two or more.

In further embodiments, the resultant liquid form from the colchicinedescribed herein comprises a coloring agent for identity and/oraesthetic purposes. Suitable coloring agents approved by the U.S. Foodand Drug Administration (FDA) include FD&C Red No. 3, FD&C Red No. 20,FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5,D&C Orange No. 5, D&C Yellow No. 10, caramel, ferric oxide and mixturesthereof.

In further embodiments, the resultant liquid form from the colchicinedescribed herein comprises a thickening agent. Thickening agentsinclude, but are not limited to xanthan gum.

In some embodiments other flavoring agents, buffering systems, andpreservatives may be used. The solution is formulated to inhibit growthof bacteria, mold, and yeast for storage at room temperature and ambientconditions.

In some embodiments, the liquid formulation includes 0.2-0.4% w/v ofbenzyl alcohol, 0.1-0.3% w/v of anhydrous citric acid, 0.005-0.025% w/vof colchicine, 0.005-0.02% w/v of dye, 0.8-1.6% w/v or dibasic sodiumphosphate, heptahydrate, 0.75-0.15% w/v of flavor 825.662, 2-8% w/v ofpropylene glycol, 2-10% glycerin, 0.1-0.2% w/v of sweetener, 0.1-0.2%w/v of xanthan gum, and water. In other embodiments, the formulationincludes 0.28-3.2 or 0.3% w/v of benzyl alcohol, 0.2% w/v of anhydrouscitric acids, 0.012% w/v of colchicine, 0.01% w/v of FD&C Red No. 40,1.2% w/v or dibasic sodium phosphate, heptahydrate, 0.125% w/v of flavorcherry 825.662, 5% w/v of propylene glycol, 0.15% w/v of sucralose,0.15% w/v of xanthan gum, and water.

An exemplary formulation includes benzyl alcohol (0.3% w/v), Citric Acid(0.2% w/v), dye (0.01% w/v), Dibasic Sodium Phosphate, Heptahydrate(0.125% w/v), propylene glycol (5% w/v), glycerin (5% w/v), sweetener(0.15% w/v), xanthan gum (0.15% w/v), and water. The formulation mayinclude Colchicine (0.012% w/v).

The colchicine described herein is stable in various storage conditionsincluding refrigerated, ambient, and accelerated conditions. Stable asused herein refers to the ability of an active agent to maintainactivity under standard stability conditions. Standard stabilityconditions include relative humidity conditions along with thetemperatures, 25 degrees C. 60% RH(RT), 30 C 65% RH (ICH), and 40 C 75%RH (accelerated), for example.

At refrigerated and ambient conditions, the liquid colchicinecomposition described herein in stable for at least 1 month, at least 2months, at least 3 months, at least 6 months, at least 9 months, atleast 12 months, at least 15 months, at least 18 months, and at least 24months. At accelerated conditions, the colchicine solution describedherein is stable for at least 1 month, at least 2 months, at least 3months and at least 6 months. Accelerated conditions includetemperatures that are above ambient levels. In some instances, anaccelerated condition is at about 30° C., about 35° C., about 40° C.,about 45° C., about 50° C., about 55° C., or about 60° C. Ambientconditions include temperature that is at ambient levels. In someinstances, an ambient condition is at about 20° C., about 21° C., about22° C., about 23° C., about 24° C., about 25° C., about 26° C., about27° C., about 28° C., about 29° C., and about 30° C. Refrigeratedconditions include temperature in typical refrigeration units (e.g. 5±3°C.). In some instances, a refrigerated condition is about 2° C., about3° C., about 4° C., about 5° C., about 6° C., about 7° C., or about 8°C.

Liquid vehicles suitable for the colchicine described herein areselected for a particular oral liquid composition (e.g., solution,suspension, etc.) as well as other properties such as clarity,viscosity, compatibility with excipients, chemical inertness,palatability, odor, and color. Exemplary liquid vehicles include water,ethyl alcohol, glycerin, propylene glycol, syrup (e.g., sugar or othersweetener based, e.g., Ora-Sweet® SF sugar-free flavored syrup), juices(e.g., apple, orange, cranberry, cherry, tomato and the like), otherbeverages (e.g., tea, coffee, soft drinks, milk and the like), oils(e.g., olive, soybean, corn, mineral, castor and the like), andcombinations or mixtures thereof. Certain liquid vehicles, e.g., oil andwater, can be combined together to form emulsions. In some embodiments,water is used as a vehicle for a colchicine oral liquid. In otherembodiments, propylene glycol is used as a vehicle for a colchicine oralliquid. For the liquid colchicine described herein, the solutioncomponent is used as the vehicle for a colchicine oral liquid.

The viscosity of the solution is an important component. In someembodiments the solution has a viscosity in the range of 40-800 cps. Inother embodiments the solution has a viscosity of 80-250 cps.

The colchicine oral liquid compositions may be used for the treatment ofdiseases and conditions described herein. In addition, a method fortreating any of the diseases or conditions described herein in a subjectin need of such treatment involves administration of colchicine oralliquid compositions in therapeutically effective amounts to the subject.In some embodiments, the amount of a given colchicine oral liquidcomposition that corresponds to such an amount varies depending onfactors such as the particular colchicine salt or form, diseasecondition and its severity, the identity (age, weight, sex) of thesubject or patient in need of treatment, but can nevertheless bedetermined according to the particular circumstances surrounding thecase, including, e.g., the specific agent being administered, the liquidcomposition type, the condition being treated, and the subject orpatient being treated.

In further embodiments, the daily dosages appropriate for the colchicineoral liquid compositions described herein are from about 0.5 mg-2.4mg/day, or in other embodiments 0.2 mg-1.5 mg/dose/day or in otherembodiments 0.5 mg-1.5 mg/dose/day. In one embodiment, the daily dosageappropriate for the colchicine liquid compositions is about 0.6-1.2mg/dose/day.

Typically, daily dosages should be considered when colchicine oralsolution is co-administered with other drugs, particularly CYP3A4 orPgP-glycoprotien inhibitors. Typically, the daily dosage of theposaconazole (a strong CYP3A4 inhibitor) dose is 300 mg/day to 600mg/day. A first dose of 300 mg on the first day followed by a seconddose on the first day may be administered. In some embodiments the dailydose delivered after the first day is 300 mg/day. The tablets areavailable as 100 mg tablets, and mutiple tablets may be administered ata time. The daily dosage for a moderate CYP3A4 inhibitor such asciprofloxacin hydrochloride is generally one 500 mg Cipro®(ciprofloxacin hydrochloride. The daily dosage for a weak CYP3A4inhibitor such as amlodipine besylate is typically 5 mg once daily witha maximum dose of 10 mg once daily. The daily dosage for a moderate P-gpinhibitor such as carvedilol phosphate is generally a single daily oraldose of Coreg CR® (carvedilol phosphate) Extended Release Capsule, 20mg.

The treatment of certain diseases or conditions (e.g., gout, FMF,cardiac disease etc.) in a patient or subject with a colchicine oralliquid composition described herein encompass additional therapies andtreatment agents in some embodiments. Such additional therapies andtreatment regimens include another therapy, e.g., antibiotics, for thetreatment of the particular disease in some embodiments.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice of testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue. The use of the term “or” in the claims is used to mean “and/or”unless explicitly indicated to refer to alternatives only or thealternatives are mutually exclusive, although the disclosure supports adefinition that refers to only alternatives and to “and/or”. The terms“comprise”, “have”, and “include” are open-ended linking verbs. Anyforms or tenses of one or more of these verbs “comprises,” “comprising,”“has,” “having,” “includes,” and “including” are also open-ended. Forexample, any method that “comprises,” “has” or “includes” one or moresteps is not limited to possessing only those one or more steps and alsocovers other unlisted steps.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the description includes instances where the events occurs andinstances where it does not.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In some embodiments, a therapeutic agent such as oralcolchicine is directed to the treatment and/or the amelioration of,reversal of, or stabilization of the symptoms of gout, familialMediterranean fever (FMF), pericarditis, Behçet's disease, atrialfibrillation, amyloidosis, calcium pyrophosphate deposition disease(pseudogout), cirrhosis of the liver, sarcoid arthritis, andinflammatory diseases described herein.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. Thus, as used herein, the term “administering”, when used inconjunction with an oral colchicine composition, can include, but is notlimited to, providing an oral colchicine composition into or onto thetarget tissue; providing an oral colchicine composition systemically toa patient by, e.g., oral administration whereby the therapeutic reachesthe target tissue or cells. “Administering” a composition may beaccomplished by injection, topical administration, and oraladministration or by other methods alone or in combination with otherknown techniques.

As used herein, the terms “patient,” “subject” and “individual” areintended to include living organisms in which certain conditions asdescribed herein can occur. The term patient, as used herein, refers tohuman patients. Examples include humans, monkeys, cows, sheep, goats,dogs, cats, mice, rats, and transgenic species thereof. In a preferredembodiment, the patient is a primate. In certain embodiments, theprimate or subject is a human. In certain instances, the human is anadult. In certain instances, the human is child. In certain instances,the human is elderly. In other instances, the human is 65 years of ageor older. Other examples of subjects include experimental animals suchas mice, rats, dogs, cats, goats, sheep, pigs, and cows. By“pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

Embodiments have been described where the techniques are implemented incircuitry and/or computer-executable instructions. It should beappreciated that some embodiments may be in the form of a method, ofwhich at least one example has been provided. The acts performed as partof the method may be ordered in any suitable way. Accordingly,embodiments may be constructed in which acts are performed in an orderdifferent than illustrated, which may include performing some actssimultaneously, even though shown as sequential acts in illustrativeembodiments.

Various aspects of the embodiments described above may be used alone, incombination, or in a variety of arrangements not specifically discussedin the embodiments described in the foregoing and is therefore notlimited in its application to the details and arrangement of componentsset forth in the foregoing description or illustrated in the drawings.For example, aspects described in one embodiment may be combined in anymanner with aspects described in other embodiments.

The present invention is further illustrated by the following Examples,which in no way should be construed as further limiting. The entirecontents of all of the references (including literature references,issued patents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated by reference.

EXAMPLES Example 1

Study-001; A Randomized, Open-Label, Single-Dose, 3-Way, RelativeBioavailability Human Clinical Study

The study examined the bioavailability of Colchicine Oral Solution 0.6mg (0.12 mg/mL, 5 mL) under Fed and Fasted Conditions in comparison toProbenecid and Colchicine Tablets, USP (500 mg/0.5 mg) under FastedConditions in Healthy Adult Volunteers The primary study objectivesincluded: 1) determining the relative bioavailability of Colchicine OralSolution 0.6 mg (0.12 mg/mL, 5 mL) and Probenecid and ColchicineTablets, USP (500 mg/0.5 mg) under fasted conditions in healthy adultmale and female volunteers; and 2) assessing the effect of food on theabsorption of Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL) byadministration of the formulation under fed versus fasted conditions inhealthy adult male and female volunteers. Secondary study objectionsincluded the evaluation and comparison of the safety and tolerability ofsingle oral doses of Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL)and Probenecid and Colchicine Tablets, USP (500 mg/0.5 mg) in healthyadult male and female volunteers.

Methods:

This was an open-label, single dose, randomized, three-period, crossoverdesign study to evaluate the relative bioavailability of a single oraldose of Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL) and a singleoral dose of one Probenecid and Colchicine Tablets, USP (500 mg/0.5 mg)under fasted conditions in healthy male and female subjects.Furthermore, the study evaluated the food effect of a single oral doseof Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL) under fed andfasted conditions. Following a screening period of up to 21 days, atotal of 36 healthy, non-smoking, adult, male and female subjects wereenrolled. Total study participation was approximately 37 days (excludingup to 21 of screening). During this time, subjects were confined to theClinical Research Unit (CRU) for 3 study periods for approximately 4days (3 nights) on each period.

Eligible subjects received single oral doses of one of three study drugs(Treatment A, B or C) on three separate Periods in a randomly assignedsequence, with each treatment separated by an approximate 14-day washoutperiod. In each study period (Day 1 of Periods 1, 2 and 3), dosingoccurred in the morning after an overnight fast of at least 10 hours.For study drug administered under fasted conditions, subjects receivedtheir assigned dose of study drug after an overnight fast. Studymedication was administered with 240 mL water.

-   -   A: Test (Fasted): Single oral dose of Colchicine Oral Solution        0.6 mg (0.12 mg/mL, 5 mL) under fasted conditions    -   B: Test (Fed): Single oral dose of Colchicine Oral Solution 0.6        mg (0.12 mg/mL, 5 mL) under fed conditions    -   C: Reference (Fasted): Single oral dose of Probenecid and        Colchicine Tablets, USP (500 mg/0.5 mg) under fasted conditions

For study drug administered under fed conditions, subjects were given ahigh-fat, high-calorie (HFHC) meal after an overnight fast of at least10 hours; each subject started consuming this meal 30 minutes prior tostudy drug administration and completed the entire meal at least 5minutes prior to dosing. Study drug was then administered with 240 mL ofwater.

Each subject was randomized to one of three treatment sequences (ABC,BCA, CAB) with 12 subjects per sequence, according to a randomizationschedule prepared prior to the start of the study (Period 1, 2 and 3).During each of the 3 study periods, confinement began at approximately1400 hours on the day prior to dosing and continued until after the 48 hpharmacokinetic (PK) post dose sampling and safety assessments. Subjectswere allowed to exit the CRU and then return on an outpatient basis forthe 72 h, 96 h and 120 h PK sampling and safety assessments.

Fed Conditions Dosing Session: Following an overnight fast of at least10 hours, subjects began consuming a HFHC breakfast approximately 30minutes prior to dosing and completely consumed the meal approximately 5minutes prior to dosing. Subjects then received a single oral dose oftheir assigned study drug with approximately 240 mL room temperaturewater at approximately 0800 hours (±1 hour).

Fasted Conditions Dosing Sessions: Following an overnight fast of atleast 10 hours, subjects received a single oral dose of their assignedstudy drug with approximately 240 mL room temperature water atapproximately 0800 hours (±1 hour).

In each of the 3 study periods, serial PK blood samples to measureplasma concentrations of colchicine were collected by directvenipuncture or by use of an indwelling catheter prior to dosing (up to60 minutes prior to dosing) and at, 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2,2.5, 3, 4, 6, 8,

12, 16, 24, 36, 48, 72, 96 and 120 hours post dose. Where PK samplingtime points coincide with vital sign measurements, vital signs werecollected within 10 minutes prior to the scheduled time point, and PKsamples were obtained at the scheduled time point.

Height and weight were measured and body mass index (BMI) was calculatedat Screening. A full physical examination (PE) was performed atScreening, and an abbreviated PE was performed at the Check-in Visit ofeach Period and at the Study Exit/Early Termination Visit. PEs wererepeated prior to study discharge as deemed necessary by theInvestigator or in response to adverse events (AEs).

Pharmacokinetic Assessments:

Plasma concentrations of colchicine was measured. Pharmacokineticparameters for colchicine including C_(max), t_(max), AUC_(0-t),AUC_(0-inf), K_(el) and t_(1/2) were calculated using anon-compartmental analysis method.

Statistical Methods and Data Analysis

Two analysis populations were used to summarize the results from thisstudy.

Safety/Toxicity (Adverse Events) Population:

All subjects who received at least one dose of study drug were assessed.

PK Population:

All subjects who completed all three treatment periods without any majorprotocol violations, who had sufficient plasma colchicine concentrationdata for reliable estimates of the key pharmacokinetic variables, andwho did not vomit within 3 hours of dosing.

The primary PK endpoints were maximum plasma colchicine concentration(C_(max)) and area under the plasma drug concentration versus time curvecalculated to the last measurable observation (AUC_(0-t)). Secondary PKendpoints were dose-normalized AUC extrapolated to infinity(AUC_(0-inf), and time to C_(max) (T_(max)), elimination half-life(t_(1/2)) and terminal elimination rate constant (K_(el)).

Relative Bioavailability Comparison of Test Vs. Reference Formulations:

The relative bioavailability of the Test and Reference formulations werecompared; more specifically, the Test formulation—Colchicine OralSolution 0.6 mg (0.12 mg/mL, 5 mL) was compared to the Referenceformulation—Probenecid and Colchicine Tablets USP (500 mg/0.5 mg), withboth formulations administered under fasted conditions. Plasmacolchicine C_(max) and AUC values were dose-normalized.

Results

The human clinical trial (Study-001) was a 3-way crossover study ofProbenecid and Colchicine Tablets USP, 500/0.5 mg reference formulationin the fasted state following a 10-hour overnight fast vs. a single doseof Colchicine Oral Solution (i.e. liquid colchicine solution of theinvention), 0.6 mg (0.12 mg/mL, 5 mL) test formulation in the fastedstate following a 10-hour overnight fast vs. a single dose of ColchicineOral Solution following a standard FDA high-fat meal.

Safety/Toxicity (Adverse Events) Results

A total of 36 human patients were randomized in the study, of which 34subjects (94.4%) were included in the PK population and all 36 subjects(100%) were included in the safety population. Two (2) subjects (5.6%)discontinued prematurely from the study, one subject requested to bewithdrawn from the study and the other was noncompliant with the studyprotocol. Single doses of Colchicine Oral Solution and Probenecid andColchicine Tablets were safely administered and generally well toleratedin these healthy adult subjects.

PK Results

Mean colchicine plasma concentrations vs. time profiles are shown inFIG. 1 on a semi logarithmic scale. A summary of the PK parameters forcolchicine is displayed in Table 1. Similar PK profiles suggest thatcolchicine absorption in the oral solution (Test) was similar to thetablet formulation (Reference). Median T_(max) for the oral solution wasthe same as the tablet formulation (1 hour). The apparent terminalhalf-life (31 hours) of colchicine oral solution was also similar to thetablet formulation (31 hours). Dose-normalized colchicine mean C_(max)for Treatment A (3.60 ng/mL) was similar to the dose-normalized C_(max)for Treatment C (3.66 ng/mL). Dose-normalized colchicine mean AUC_(0-t)for Treatment A (31.0 h·ng/mL/mg) was similar to that of Treatment C(31.1 h·ng/mL/mg). In the fed state, median T_(max) increased to 2 hourscompared to 1 hour in the fasted state. The mean C_(max) was 78.0% whencomparing fed state to fasted state and the mean AUC_(0-t) was 92.5%when comparing fed state to fasted state.

TABLE 1 Summary of PK Parameters by Treatment - PK Population Probenecidand Colchicine Oral Colchicine Oral Colchicine Tablets, Solution, 0.6 mgSolution, 0.6 mg 500 mg/0.5 mg Parameter Statistic (0.12 mg/mL, 5 mL)(0.12 mg/mL, 5 mL) Fasted (N = 34) AUC_(0-t) (h · ng/mL) Mean (SD) 18.59(4.635) 17.20 (4.231) 15.54 (5.021) AUC_(0-t)/Dose Mean (SD) 30.98(7.726) 28.67 (7.052) 31.07 (10.04) (h · ng/mL/mg) AUC_(0-inf) (h ·ng/mL) Mean (SD) 19.90 (4.736) 18.47 (4.290) 16.70 (4.988)AUC_(0-inf)/Dose Mean (SD) 33.18 (7.897) 30.79 (7.162) 33.40 (9.985)(h*ng/mL/mg) C_(max) (ng/mL) Mean (SD) 2.161 (0.8741) 1.685 (0.3945)1.828 (0.7096) C_(max)/Dose Mean (SD) 3.602 (1.457) 2.809 (0.6575) 3.655(1.419) (ng/mL/mg) T_(max) (h) Median (Min-Max) 1.00 (0.50: 2.00) 2.00(1.00: 4.00) 1.00 (0.50: 1.75) t_(1/2) (h) Mean (SD) 31.04 (5.988) 30.54(5.219) 31.20 (6.770) K_(el) (1/h) Mean (SD) 0.0232 (0.0049) 0.0233(0.0036) 0.0231 (0.0046) A: Colchicine Oral Solution 0.6 mg (0.12 mg/mL,5 mL), Fasted; B: Colchicine Oral solution 0.6 mg (0.12 mg/mL, 5 mL),Fed C: Probenecid and Colchicine Tablets, 500 mg/0.5 mg, Fasted

Bioavailability Results

A summary of relative bioavailability analyses for Colchicine OralSolution vs. tablets and Colchicine Oral Solution fasted vs. fed aredisplayed in Table 2 and Table 3, respectively. Dose-normalized relativebioavailability of colchicine oral solution was 101.2 (90% CI:94.05-109.0) for AUC_(0-t) ratio and 98.45% (90% CI: 88.47-109.6%) forC_(max) ratio. With respect to the bioequivalence analysis of TreatmentA vs. Treatment C, the 90% CIs for C_(max), AUC_(0-t) and AUC_(0-inf)were contained within the pre-defined limit of 80 to 125% forcolchicine.

TABLE 2 Summary of Dose Normalized Relative Bioavailability Analysis forTest vs. Reference of Colchicine - PK Population (Study-001) 90% CIIntra- GMR (%) Subject normalized n A n C A/C A/C CV % C_(max)/Dose 343.356 34 3.408 98.45 (88.47- 26.86 (ng/mL/mg) 109.6) AUC_(0-t)/Dose 3430.09 34 29.72 101.2 (94.05- 18.33 (ng · hr/ 109.0) mL/mg)AUC_(0-inf)/Dose 34 32.32 34 32.16 100.5 (93.86- 16.95 (ng · hr/ 107.6)mL/mg) A: Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL), Fasted C:Probenecid and Colchicine Tablets, 500 mg/0.5 mg, Fasted

TABLE 3 Dose Normalized Food Effect Evaluation of Colchicine TestFormulation 90% CI Intra- GMR (%) Subject normalized n A n B B/A B/A CV% C_(max)/Dose 34 3.356 34 2.731 81.37 (73.12- 26.86 (ng/mL/mg) 90.55)AUC_(0-t)/Dose 34 30.09 34 27.80 92.40 (85.84- 18.33 (ng · hr/ 99.46)mL/mg) AUC_(0-inf)/Dose 34 32.32 34 29.99 92.79 (86.68- 16.95 (ng · hr/99.33) mL/mg) A: Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL),Fasted B: Colchicine Oral Solution 0.6 mg (0.12 mg/mL, 5 mL), Fed

Conclusions

The comparisons of colchicine exposure (dose normalized C_(max),AUC_(0-t) and AUC_(0-inf)) between the test (oral solution) andreference formulation (tablet) satisfied the bioequivalence criteria asC_(max), AUC_(0-t) and AUC_(0-inf) GMRs were fully contained within the80 to 125% boundaries. The study showed that a minimum food effect wasobserved when colchicine oral solution was administered following a highfat high calorie meal. A slight decrease in C_(max) was observed;however, the overall extent of absorption, based on GMRs for AUC_(0-t)and AUC_(0-inf), was similar in the fed and fasted states.

Example 2

Study-002

Study-002 was an open-label, 2-period, sequential human clinical studyto assess the effects of multiple oral doses of Coreg CR® (carvedilolphosphate) Extended-Release Capsules on the PK of a single oral dose ofColchicine Oral Solution, 0.6 mg (0.12 mg/mL, 5 mL) in healthy male andfemale adult volunteers. The study was designed to assess the effects ofcarvedilol phosphate, a known inhibitor of the P-gp transporter, on thePK of colchicine, a known P-gp substrate. The dosing scheme for thisstudy is illustrated in Table 4. In each of the two treatment periods,serial PK blood samples to measure plasma concentrations of colchicinewere collected prior to dosing (0 hour, up to 60 minutes prior todosing) and at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48,72 and 96 hours post dose.

TABLE 4 Study-002 Dosing Scheme Period, Day Treatments and PK SamplingDescription Period 1, Single oral dose of Colchicine Oral Solution, Day1 0.6 mg (0.12 mg/mL, 5 mL) at approximately 08:00 hours administered 30minutes following a standard breakfast Period 1, Washout period betweentreatments Days 2 to 10 Period 2, Single daily oral doses of Coreg CR ®Days 11 to 12 (carvedilol phosphate) Extended-Release Capsule, 20 mg atapproximately 08:00 hours administered 30 minutes following a standardbreakfast Period 2, Single daily oral dose of Coreg CR ® Days 13 to 16(carvedilol phosphate) Extended-Release Capsule, 40 mg at approximately08:00 hours each morning administered 30 minutes following a standardbreakfast Period 2, Single oral dose of Colchicine Oral Solution, Day 170.6 mg (0.12 mg/mL, 5 mL) with a single oral dose of Coreg CR ®(carvedilol phosphate) Extended-Release Capsule, 40 mg at approximately08:00 hours administered 30 minutes following a standard breakfast

A total of 24 healthy adult subjects were dosed on the study, of which21 subjects (87.5%) completed study treatment per protocol; 3 subjects(12.5%) discontinued prematurely from the study due to positive drugscreen, noncompliance with the protocol and withdrawal of consent. All24 subjects (100.0%) were included in the safety and PK populations.Twenty-one (21) subjects (87.5%) were included in the drug-druginteraction (DDI) assessment of the Coreg CR® impact on the plasma PK ofcolchicine.

Safety/Toxicity (Adverse Events) Results

Single doses of Colchicine Oral Solution administered with and withoutcarvedilol phosphate (Coreg CR®) were safely administered and generallywell tolerated in these healthy adult subjects.

PK Results

Mean colchicine plasma concentrations vs. time profiles are shown inFIG. 2 on a semi-logarithmic scale. A summary of the PK parameters forcolchicine is provided in Table 5.

Similar PK profiles were observed for Colchicine Oral Solution whenadministered alone and when co-administered with carvedilol phosphate.When colchicine was co-administered with carvedilol phosphate, theterminal phase profile was slightly higher than colchicine alone, butboth terminal phase profiles were parallel. The median t_(max) value forcolchicine alone and with the concomitant use of carvedilol phosphatewas the same. The apparent terminal half-life (˜31 hours) of colchicinealone was also similar to the co-administration with carvedilolphosphate (˜32 hours). The mean C_(max) value for colchicine alone(1.973 ng/mL) was similar to the C_(max) value for co-administrationwith carvedilol phosphate (1.920 ng/mL). Mean AUC_(0-last) forcolchicine co-administration with carvedilol phosphate (22.06 h·ng/mL)was 23% higher than that of colchicine alone (17.91 h·ng/mL).

Given that colchicine is a known substrate for P-gp, it is hypothesizedthat an inhibitor of P-gp such as carvedilol phosphate could potentiallyaffect the PK profile of colchicine. In this study, it was surprisinglydemonstrated that carvedilol phosphate had no effect on the C_(max) ofcolchicine. The percent GMR of AUC_(0-last) (co-administration withcarvedilol phosphate/colchicine alone) was 117.9% and its 90% CI was inthe range of 112.0%-124.1%. The 90% CIs for C_(max), AUC_(0-last) andAUC_(0-inf) were contained within the 80 to 125% boundaries.

TABLE 5 Summary of Colchicine PK Parameters - PK Population ColchicineOral Colchicine Oral Solution, 0.6 mg Solution, 0.6 mg (0.12 mg/mL, 5mL) + (0.12 mg/mL, 5 mL) Coreg CR ® 40 mg Parameter Statistic (N = 24)(N = 21) AUC_(0-last) (h*ng/mL) Mean (SD) 17.91 (4.169) 22.06 (5.531)Ln(AUC_(0-last)) Mean (SD) 2.858 (0.2413) 3.061 (0.2697) AUC_(0-inf)(h*ng/mL) Mean (SD) 19.69 (4.523) 24.23 (5.879) Ln(AUC_(0-inf)) Mean(SD) 2.954 (0.2359) 3.156 (0.2652) C_(max) (ng/mL) Mean (SD) 1.973(0.4818) 1.920 (0.5240) Ln(C_(max)) Mean (SD) 0.6536 (0.2270) 0.6178(0.2690) T_(max) (h) Median (Min-Max) 2.00 (1.00, 4.00) 2.00 (0.75,3.00) AUC_(0-last/)AUC_(0-inf) (%) Mean (SD) 89.91 (5.441) 90.96 (2.708)Vz/F (L) Mean (SD) 1420 (329.9) 1233 (405.3) CL/F (L/h) Mean (SD) 32.12(7.736) 26.48 (7.835) Kel (1/h) Mean (SD) 0.0230 (0.0043) 0.0220(0.0035) t_(1/2) (h) Mean (SD) 31.13 (5.560) 32.22 (4.895)

Effect of Carvedilol Phosphate on Colchicine PK Results

Carvedilol phosphate had no significant effect on the plasma C_(max) andAUC parameters of colchicine (Table 6). The 90% CIs for C_(max),AUC_(0-last) and AUC_(0-inf) were contained within the pre-defined 80 to125% boundaries.

TABLE 6 Effect of Coreg CR ® (carvedilol phosphate) on the Plasma PK ofColchicine - DDI Assessment (Study-002) GMR GMR 90% CI Intra- PK LeastSquare Geometric Means (%) (%) Subject Parameter N T n R T/R T/R CV %C_(max) 21 1.855 21 1.940 95.59 (89.64- 12.11 (ng/mL) 101.9)AUC_(0-last) 21 21.35 21 18.11 117.9 (112.0- 9.673 (ng · 124.1) h/mL)AUC_(0-inf) 19 23.54 19 19.99 117.8 (111.8- 9.220 (ng · 124.0) h/mL) R:Colchicine Oral Solution, 0.6 mg (0.12 mg/mL, 5 mL) T: Colchicine OralSolution, 0.6 mg (0.12 mg/mL, 5 mL) + Coreg CR ®, 40 mg

Conclusions

No significant drug interaction was observed for Colchicine OralSolution when administered with the P-gp inhibitor, carvedilolphosphate, based on the 90% CIs for the C_(max), AUC_(0-last) andAUC_(0-inf) GMRs being fully contained within the 80 to 125%bioequivalence boundaries.

Colchicine Oral Solution was well tolerated in the study whenadministered as a single oral 0.6 mg dose alone and in combination withmultiple doses of carvedilol phosphate extended-release capsules. Nosafety concerns were raised during the study. No subject discontinuedthe study drug due to an AE. There were no SAEs reported in the study.

Example 3

Study-003

Study-003 was a three cohort, open-label, 2-period, sequential humanclinical study to assess the effects of multiple oral doses of Noxafil®(posaconazole) Delayed Release Tablets, Cipro® (ciprofloxacinhydrochloride) Tablets, and Norvasc® (amlodipine besylate) tablets onthe PK of a single oral dose of Colchicine Oral Solution, 0.6 mg (0.12mg/mL, 5 mL) in healthy male and female adult volunteers. The study wasdesigned to assess the effects of strong (posaconazole), moderate(ciprofloxacin hydrochloride) and weak (amlodipine besylate) CYP3A4inhibitors, on the PK of colchicine, a known CYP3A4 substrate. Thedosing scheme and serial blood PK sampling schedule for this study byperiod and cohort is outlined in Table 7.

TABLE 7 Study-003 Dosing Scheme and Sampling Schedule Period, Day Cohort1 Cohort 2 Cohort 3 Period 1, Single oral dose of Colchicine OralSolution, 0.6 mg (0.12 mg/mL, 5 mL) at approximately Day 1 08:00 hoursadministered 30 minutes following a light breakfast for Cohort 1 andfollowing an overnight fast in Cohorts 2 and 3, such that dosingconditions relative to fed or fasted state are identical within a cohortfor Periods 1 and 2. Serial PK samples for plasma colchicineconcentration determination following Day 1 dosing will be obtained at0, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, and 96hours postdose (Days 1, 2, 3, 4 and 5). Period 1, Washout period betweentreatments Days 2 to 10 Period 2, On Day 11, each subject On Days 11-16,each subject On Days 11-13, each subject Days 11to 16 will receive 300mg will receive one 500 mg will receive a 5 mg for Cohorts 1 Noxafil ®(posaconazole) Cipro ® (ciprofloxacin Norvasc ® (amlodipine and 2, (100mg × 3) delayed-release hydrochloride) tablet at besylate) tablet at8:00 a.m., Days 11 to 19 tablets at 8:00 a.m. and 8:00 a.m. and at 8:00p.m. in then if tolerated based on for Cohort 3 6:00 pm, then on Daysthe fasted state, following an vital signs assessments and 12-16, eachsubject will overnight fast of at least 10 overall safety and receive a300 mg Noxafil ® hours. tolerability assessments, on (posaconazole) ®dose at 8:00 Days 14-19, subjects will a.m. following a light receive a10 mg Norvasc ® breakfast. (amlodipine besylate) tablet at 8:00 a.m. inthe fasted state following an overnight fast of at least 10 hours.Period 2, Day On Day 17, each subject On Day 17, each subject On Day 20,each subject 17 for will receive both one dose will receive both onedose will receive both one dose of Cohorts 1 and of 0.6 mg colchicineoral of 0.6 mg colchicine oral 0.6 mg colchicine oral 2, Day 20 forsolution and a 300 mg solution and a 500 mg solution and a 10 mg Cohort3 Noxafil ® (posaconazole) Cipro ® (ciprofloxacin Norvasc ® (amlodipine(100 × 3) dose at 8:00 a.m. hydrochloride)dose at 8:00 besylate) tabletdose at following a light breakfast. a.m. following an overnight 8:00a.m. in the fasted state fast of at least 10 hours and following anovernight fast a final dose of Cipro ® of at least 10 hours. 500 mg at8:00 p.m. (without colchicine). Period 2, Serial PK samples for SerialPK samples for Serial PK samples for serial PK plasma colchicine plasmacolchicine plasma colchicine sampling concentration determinationconcentration determination concentration determination following lastwill be obtained following will be obtained following will be obtainedfollowing dose of Day 17 dosing at 0, 0.5, Day 17 dosing at 0, 0.5, Day20 dosing at 0, 0.5, Colchicine + 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 0.75,1, 1.25, 1.5, 2, 3, 4, 6, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, CYP3A4 8, 12,24, 36, 48, 72, and 96 8, 12, 24, 36, 48, 72, and 96 8, 12, 24, 36, 48,72, and 96 inhibitor hours postdose (Days 17, hours postdose (Days 17,hours postdose (Days 20, 18, 19, 20 and 21). 18, 19, 20 and 21). 21, 22,23 and 24).

1. Cohort 1: Effect of the Strong CYP3A4 Inhibitor (Posaconazole) onColchicine PK

A total of 24 healthy adult subjects were dosed in each cohort on thestudy. Twenty-two (22) subjects (91.7%) completed study treatment perprotocol. Two (2) subjects (8.3%) discontinued prematurely from thestudy due to noncompliance with the protocol and withdrawal of consent.Twenty-four (100%) overall subjects were included in the safety and PKpopulation; and twenty-two (22) (91.7%) subjects were included in theDDI assessment of the combined posaconazole and colchicine dosing.

Safety/Toxicity (Adverse Events) Results

Single doses of Colchicine Oral Solution administered with and withoutposaconazole (Noxafil®) were safely administered and generally welltolerated in these healthy adult subjects.

PK Results

The data with posaconazole is shown in FIG. 3 and Table 8. The GMRvalues and 90% CI's for C_(max) and AUC_(0-last) fell outside the 80 to125% boundaries for bioequivalence (Table 9). The terminal half-liferemained unchanged when Colchicine Oral Solution was administered alone(32.86 hours) or with posaconazole (32.51 hours). These results showthat colchicine plasma levels are markedly elevated (by approximately3.1 fold) in the presence of a strong CYP3A4 inhibitor. The combinationof colchicine+posaconazole was generally well-tolerated, however due tothe 3.1 fold increase in colchcine plasma levels, a dose adjustment to 2mL daily is recommended when co-administering colchicine oral liquid andposaconazole.

TABLE 8 Summary of PK Parameters - PK Population (Study-003, Cohort 1 -Strong CYP3A4 Inhibitor: Posaconazole) Colchicine Oral Solution, 0.6 mgColchicine Oral (0.12 mg/mL, 5 mL) + Solution, 0.6 mg Noxafil ®(posaconazole), (0.12 mg/mL, 5 mL) 300 mg (100 mg × 3) ParameterStatistic Fed (N = 24) Fed (N = 22) AUC_(0-last) (h · ng/mL) Mean (SD)15.28 (3.904) 47.14 (13.50) Ln(AUC_(0-last)) Mean (SD) 2.696 (0.2553)3.815 (0.2872) AUC_(0-inf) (h · ng/mL) Mean (SD) 16.92 (4.571) 52.20(16.03) Ln(AUC_(0-inf)) Mean (SD) 2.795 (0.2661) 3.911 (0.3077) C_(max)(ng/mL) Mean (SD) 2.053 (0.5749) 4.670 (1.269) Ln(C_(max)) Mean (SD)0.6831 (0.2752) 1.504 (0.2870) T_(max) (h) Median (Min-Max) 1.25(0.75-3) 1.50 (1-3) AUC_(t/inf) (%) Mean (SD) 89.85 (4.083) 89.83(3.643) Vz/F (L) Mean (SD) 1775 (477.1) 577.7 (161.9) CL/F (L/h) Mean(SD) 37.96 (10.46) 12.58 (4.145) K_(el) (/h) Mean (SD) 1.704 (0.9902)1.657 (0.9642) t_(1/2) (h) Mean (SD) 32.86 (5.308) 32.51 (4.869)

TABLE 9 Effect of Noxafil ® (Posaconazole) on the Plasma PK ofColchicine - Cohort 1 DDI Assessment (Study-003) GMR GMR 90% CI Intra-PK Least Square Geometric Means (%) (%) Subject Parameter n T n R T/RT/R CV % C_(max) 22 4.498 22 1.980 227.1 (201.6- 23.26 (ng/mL) 255.8)AUC_(0-last) 22 45.36 22 14.60 310.7 (283.7- 17.69 (ng · h/mL) 340.4)AUC_(0-inf) 20 49.31 20 15.98 308.7 (281.0- 17.27 (ng · h/mL) 339.0) R:Colchicine Oral Solution, 0.6 mg (0.12 mg/mL, 5 mL), Fed T: ColchicineOral Solution, 0.6 mg (0.12 mg/mL, 5 mL) + Noxafil ® (posaconazole), 300mg (100 mg × 3), Fed

Conclusions (Cohort 1)

Colchicine Oral Solution was well tolerated in the study whenadministered as a single oral 0.6 mg dose alone and in combination withmultiple doses of posaconazole delayed-release tablets. No safetyconcerns were raised during the study. No subject discontinued the studyd rug due to an AE. There were no SAEs reported in the study.

The combination of colchicine+posaconazole was well tolerated, howeverdue to the 3.1 fold increase in colchicine plasma levels an initial doseadjustment for colchicine is recommended when co-administeringcolchicine with posaconazole.

2. Cohort 2: Effect of the Moderate CYP3A4 Inhibitor CiprofloxacinHydrochloride on Colchicine PK

Twenty (20) subjects (83.3%) completed study treatment per protocol.Four subjects (16.7%) discontinued prematurely from the study; 3subjects withdrew consent for personal reasons and one subject wasdiscontinued based on the investigator's conclusion that ciprofloxacinhydrochloride was not being tolerated. Twenty-four (100%) overallsubjects were included in the safety and PK population; and twenty (20)(83.3%) subjects were included in the DDI assessment of the combinedciprofloxacin hydrochloride and colchicine dosing.

Safety/Toxicity (Adverse Events) Results

Single doses of Colchicine Oral Solution administered with and withoutciprofloxacin hydrochloride (Cipro®) were safely administered andgenerally well tolerated in these healthy adult subjects.

PK Results

As shown in FIG. 4 and Table 10, ciprofloxacin hydrochloride had nomarked effects on the mean C_(max), AUC_(0-last) and terminal half-lifeof Colchicine Oral Solution. The GMR values and 90% CI's for C_(max) andAUC_(0-last) fell within the 80 to 125% boundaries for bioequivalence(Table 11) indicating that a drug-drug interaction with the moderateCYP3A4 ciprofloxacin hydrochloride was unlikely.

TABLE 10 Summary of PK Parameters - PK Population (Study-003, Cohort 2)Colchicine Oral Solution, 0.6 mg Colchicine Oral (0.12 mg/mL, 5 mL) +Solution, 0.6 mg Cipro ® (ciprofloxacin (0.12 mg/mL, 5 mL)hydrochloride), 500 mg Parameter Statistic Fasted (N = 24) Fasted (N =20) AUC_(0-last) (h · ng/mL) Mean (SD) 21.32 (6.585) 18.49 (3.431)Ln(AUC_(0-last)) Mean (SD) 3.014 (0.3127) 2.901 (0.1860) AUC_(0-inf) (h· ng/mL) Mean (SD) 23.38 (7.085) 20.30 (3.940) Ln(AUC_(0-inf)) Mean (SD)3.107 (0.3084) 2.993 (0.1972) C_(max) (ng/mL) Mean (SD) 2.689 (1.396)2.331 (0.6933) Ln(C_(max)) Mean (SD) 0.8865 (0.4438) 0.8067 (0.2844)T_(max) (h) Median (Min-Max) 1.00 (0.5-1.5) 1.00 (0.75-1.5) AUC_(t/inf)(%) Mean (SD) 91.10 (2.289) 91.03 (4.115) Vz/F (L) Mean (SD) 1284(378.1) 1332 (334.9) CL/F (L/h) Mean (SD) 28.12 (9.225) 30.66 (6.123)K_(el) (/h) Mean (SD) 0.0221 (0.0035) 0.0237 (0.0048) t_(1/2) (h) Mean(SD) 31.98 (4.445) 30.49 (6.511)

TABLE 11 Effect of Cipro ® (ciprofloxacin hydrochloride) on the PlasmaPK of Colchicine - Cohort 2 DDI Assessment (Study-003) GMR GMR 90% CIIntra- PK Least Square Geometric Means (%) (%) Subject Parameter n T n RT/R T/R CV % C_(max) 20 2.241 20 2.556 87.65 (74.25- 31.06 (ng/mL)103.5) AUC_(0-last) 20 18.19 20 20.87 87.16 (78.02- 20.47 (ng · h/mL)97.37) AUC_(0-inf) 19 19.94 19 22.68 87.92 (78.69- 19.90 (ng · h/mL)98.23) R: Colchicine Oral Solution, 0.6 mg (0.12 mg/mL, 5 mL), Fasted T:Colchicine Oral Solution, 0.6 mg (0.12 mg/mL, 5 mL) + Cipro ®(ciprofloxacin hydrochloride), 500 mg, Fasted

Conclusions (Cohort 2)

Colchicine Oral Solution was well tolerated in the study whenadministered as a single oral 0.6 mg dose alone and in combination withmultiple doses of ciprofloxacin hydrochloride tablets. No safetyconcerns were raised during the study. No subject discontinued the studydrug due to an AE. There were no SAEs reported in the study.

3. Cohort 3: Effect of the Weak CYP3A4 Inhibitor Amlodipine Besylate onColchicine PK Twenty-one (21) subjects (87.5%) completed study treatmentper protocol.

Three subjects (12.5%) discontinued prematurely from the study due toinvestigators decision and withdrawal of consent. Twenty-four (100%)overall subjects were included in the safety and PK population; andtwenty-one (21) (87.5%) subjects were included in the DDI assessment ofthe combined amlodipine besylate and colchicine dosing.

Safety/Toxicity (Adverse Events) Results

Single doses of Colchicine Oral Solution administered with and withoutamlodipine besylate (Norvasc®) were safely administered and welltolerated in these healthy adult subjects. There were no TEAEs whencolchicine was co-administered with amlodipine besylate.

PK Results

As shown in FIG. 5 and Table 12, amlodipine besylate had a modest effecton the mean C_(max) and AUC_(0-last) of Colchicine Oral Solution. Plasmacolchicine C_(max), AUC_(0-last) and AUC_(0-inf) GMRs were approximately1.09, 1.23 and 1.22-fold higher for colchicine+amlodipine besylatecompared to colchicine alone.

The upper 90% CI's for C_(max), AUC_(0-last) and AUC_(0-inf) felloutside the 80 to 125% boundaries for bioequivalence (Table 13)indicating that a drug-drug interaction with the weak CYP3A inhibitoramlodipine besylate could not be completely ruled out.

TABLE 12 Summary of PK Parameters - PK Population (Study-003, Cohort 3)Colchicine Oral Solution, 0.6 mg Colchicine Oral (0.12 mg/mL, 5 mL) +Solution, 0.6 mg Norvasc ® (amlodipine (0.12 mg/mL, 5 mL) besylate) 10mg Parameter Statistic Fasted (N = 24) Fasted (N = 21) AUC_(0-last) (h ·ng/mL) Mean (SD) 17.83 (6.496) 20.87 (4.954) Ln(AUC_(0-last)) Mean (SD)2.821 (0.3490) 3.010 (0.2466) AUC_(0-inf) (h · ng/mL) Mean (SD) 19.84(7.253) 22.84 (5.406) Ln(AUC_(0-inf)) Mean (SD) 2.929 (0.3469) 3.101(0.2409) C_(max) (ng/mL) Mean (SD) 2.183 (1.018) 2.257 (0.9128)Ln(C_(max)) Mean (SD) 0.6850 (0.4451) 0.7414 (0.3875) T_(max) (h) Median(Min-Max) 1.00 (0.75-1.5) 1.00 (0.75-4) AUC_(t/inf) (%) Mean (SD) 89.95(4.231) 90.61 (5.173) Vz/F (L) Mean (SD) 1618 (661.8) 1275 (491.2) CL/F(L/h) Mean (SD) 33.93 (11.43) 27.76 (6.808) K_(el) (/h) Mean (SD) 0.0218(0.0048) 0.0230 (0.0046) t_(1/2) (h) Mean (SD) 33.34 (7.603) 31.46(6.869)

TABLE 13 Effect of Norvasc ® (amlodipine besylate) on the Plasma PK ofColchicine - Cohort 3 DDI Assessment (Study-003) GMR GMR 90% CI Intra-Least Square Geometric (%) (%) Subject n T n R T/R T/R CV % C_(max) 212.099 21 1.921 109.2 (93.52- 29.83 (ng/mL) 127.6) AUC_(0-last) 21 20.2921 16.46 123.3 (110.8- 20.26 (ng · 137.1) h/mL) AUC_(0-inf) 20 22.23 2018.27 121.7 (109.1- 20.15 (ng · h/mL) 135.7) R: Colchicine, 0.6 mg,Fasted T: Colchicine, 0.6 mg + Norvasc ® (amlodipine besylate), 10 mg,Fasted

Conclusions (Cohort 3)

A small increase in exposure was observed when Colchicine Oral Solutionwas administered with the weak CYP3A4 inhibitor, amlodipine besylate.

Plasma colchicine C_(max), AUC_(0-last) and AUC_(0-inf) GMRs wereapproximately 1.09, 1.23 and 1.22-fold higher, respectively, forcolchicine+amlodipine besylate compared to colchicine alone. Althoughthe increase was surprising, the magnitude of this effect is small anddose adjustment for colchicine is not necessary when colchicine isadministered with the weak CYP3A4 inhibitor amlodipine besylate.

Colchicine Oral Solution was well tolerated in the study whenadministered as a single, oral, 0.6 mg dose alone and in combinationwith multiple doses of amlodipine besylate tablets. No safety concernswere raised during the study. No subject discontinued the study drug dueto an AE. There were no SAEs reported in the study.

Conclusions of Drug Interaction Studies

The pharmacokinetics of Colchicine Oral Solution were evaluated in thestudy following coadministration with posaconazole (a strong CYP3A4inhibitor), ciprofloxacin hydrochloride (a moderate CYP3A inhibitor),amlodipine besylate (a weak CYP3A4 inhibitor) and carvedilol phosphate(a P-gp inhibitor) to determine the effects of co-administration. Theresults were quite surprising. The blood levels of colchicine have beendemonstrated to be affected by the administration of colchicine intablet or capsule form in combination with other drugs. The results varywidely based on the drugs, but the levels of colchicine may be shiftedinto toxic levels. Significantly, the levels of colchicine when combinedwith other drugs such as CYP34A inhibitors and P-g inhibitors, remainedfairly stable, except for the combination with a strong CYP3A4inhibitor, which caused a spike in colchicine to surprisingly highlevels. These results were unexpected.

The combination of liquid colchicine with a strong CYP3A4 inhibitorproduced mean colchicine C_(max) values that were elevated byapproximately 2.3-fold from 2.053 ng/mL (alone) to 4.670 ng/mL (withposaconazole) and mean AUC_(0-last) values were elevated approximately3.1-fold from 15.28 h·mg/mL (alone) to 47.14 h·ng/mL (withposaconazole). The terminal half-life remained unchanged when ColchicineOral Solution was administered alone (32.86 hours) or with posaconazole(32.51 hours). The combination of colchicine+posaconazole was generallywell tolerated, however due to the increase in colchicine plasma levels,an initial dose adjustment for colchicine is recommended whencoadministering colchicine with posaconazole.

The combination of liquid colchicine with a moderate CYP3A4 inhibitor,Ciprofloxacin hydrochloride, resulted in no marked effects on the meanC_(max), AUC_(0-last) and terminal half-life of Colchicine OralSolution. These results indicate that significant interactions with themoderate CYP3A inhibitor ciprofloxacin hydrochloride are unlikely.

The combination of liquid colchicine with a weak CYP3A4 inhibitor,Amlodipine besylate had a modest effect on the mean C_(max)(approximately a 1.17-fold increase) and AUC_(0-last) (approximately a1.15-fold increase) of Colchicine Oral Solution. These results indicatethat significant interactions with the weak CYP3A inhibitor amlodipinebesylate are unlikely.

The combination of liquid colchicine with carvedilol phosphate had noeffect on the C_(max) of colchicine. The geometric mean percent ratio ofAUC_(0-last) (coadministration with carvedilol phosphate/colchicinealone) was 117.9% and its 90% CI was in the range of 112.0% to 124.1%.The 90% CIs for C_(max), AUC_(0-last) and AUC_(0-inf) were containedwithin the 80.00 to 125.00% limits. These results indicate that aninteraction with carvedilol phosphate is unlikely.

Example 4

Safety/Toxicity (Adverse Events) and Efficacy of Liquid ColchicineSolution

Colchicine's effectiveness as a treatment for gout has been postulatedto be due to its ability to block neutrophil-mediated inflammatoryresponses induced by monosodium urate crystals in synovial fluid.Colchicine disrupts the polymerization of β-tubulin into microtubules,thereby preventing the activation, degranulation, and migration ofneutrophils to sites of inflammation. Colchicine also interferes withthe inflammasome complex found in neutrophils and monocytes thatmediates interleukin-1β (IL-1β) activation.

Colchicine is estimated to be effective at doses of approximately 0.015mg/kg, toxic at doses greater than 0.1 mg/kg, and typically lethal atdoses of approximately 0.8 mg/kg. In the therapeutic range, plasma 1vels are in the range of approximately 0.5 to 3 ng/mL.

1. Adverse Reactions

Based on the current FDA-approved labeling for colchicine products, themost common and frequently reported adverse events of colchicine aregastrointestinal, including nausea, vomiting, abdominal pain anddiarrhea which are reversible with discontinuation of colchicine.

The following adverse events have been reported with Probenecid andColchicine Tablets USP:

1. Digestive: abdominal cramping, abdominal pain, diarrhea, lactoseintolerance, nausea, vomiting, fever

2. Neurological: headache, dizziness, peripheral neuritis

3. Dermatological: alopecia, purpura, rash, pruritus

4. Hematological: anemia, leukopenia, granulocytopenia,thrombocytopenia, pancytopenia, aplastic anemia

5. Hepatobiliary: Elevated AST/ALT

6. Musculoskeletal: myotonia, muscle weakness, muscular pain

7. Reproductive: azoospermia, oligospermia

Overdose toxicity can include severe allergic reactions and anaphylaxis,bone marrow suppression, cardiovascular collapse, renal failure,rhabdomyolysis, seizures, mental status changes and death.

2. Safety/Toxicity (Adverse Events) of Colchicine Oral Solution

Colchicine Oral Solution was well tolerated when administered orally as0.6 mg in 5 mL to healthy adult male and female subjects in thebioavailability study (Example 1) and DDI studies (Examples 2 and 3).

The most common treatment-emergent adverse event TEAEs includedheadache, dizziness and nasal congestion. All TEAEs were of mildintensity, except for one TEAE of viral infection which was moderate inintensity and considered unlikely to be related to study drug. Themajority of TEAEs were resolved at the end of the study, except for:

1. one report of a mild UTI, which was assessed as being unlikelyrelated to study drug; and

2. one subject with a mildly elevated liver enzyme test (AST) reportedat the exit visit (4 days after the last dose of study drugs), which wasassessed by as possibly related to study drug.

No subject discontinued from the studies due to an AE, and there were noSAEs or deaths reported during the studies.

Table 4 represents a summary of the data obtained in human subjectstreated with 0.6 mg colchicine prior to co-administering respectivedrugs for drug-to-drug interaction studies in comparison to publishedhuman clinical trial data for tablet and capsule formulations ofcolchicine, as detailed below.

TABLE 14 Least Square Geometric Means Cmax AUCo-t AUCo-inf Dosage Form(ng/mL) (ng · hr/mL) (ng · hr/mL) Tablets** 2.48 10.94 13.05 Capsules***2.24 16.98 19.62 Oral 2.10 17.51\ 19.23 Solution**** **Represents meanvalues from treatment 1 for 9-drug-to-drug interaction studies conductedfor Colcrys ® reported in www.clinicaltrials.gov (study numbers 16, 17,27, 28, 30, 31, 33, 35, 37 and 39). Total subjects 197. ***Representsmean values from treatment 1 for 4-drug-to-drug interaction studiesconducted for Mitigare ® reported in U.S. Pat. No. 9,555,029 B2. Totalsubjects 48. ****Represents mean values from treatment 1 for4-drug-to-drug interaction studies conducted for Colchicine OralSolution (0.12 mg/mL, 5 mL dose) by Romeg Therapeutics, LLC. Totalsubjects 84.

Table 15 depicts relative adverse events observed in human subjectstreated with 0.6 mg colchicine prior to co-administering respectivedrugs for drug-to-drug interaction studies in comparison to publishedhuman clinical trial data for tablet and capsule formulations ofcolchicine.

TABLE 15 Relative Adverse Events from Different Colchicine Dosage FormsDosage form Tablets Capsules Oral Solution Total number of 9 4 4drug-to-drug interaction studies Total number of 214 48 96 subjectsanalyzed Total number of 41 26 9 subjects reporting adverse events % ofsubjects 19.16 54.17 9.38 affected with adverse events Total number of70 57 10 adverse events reported Number of 0.33 1.19 0.10 adverseevents/subject

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

What is claimed is:
 1. A method of treating a colchicine sensitive disorder, comprising orally co-administering a liquid colchicine solution and a P-gp inhibitor to a human subject having a colchicine sensitive disorder in an effective amount to treat the disorder, wherein the colchicine sensitive disorder is selected from gout, familial Mediterranean fever (FMF), pericarditis, Behçet's disease, atrial fibrillation, amyloidosis, calcium pyrophosphate deposition disease (pseudogout), cirrhosis of the liver, or sarcoid arthritis; and wherein the liquid colchicine solution comprises a concentration of colchicine of 0.01-1.0 mg/ml, 0.1-0.3% w/v of anhydrous citric acid, 0.8-1.6% w/v of dibasic sodium phosphate heptahydrate, 0.1-0.2% w/v of a thickening agent, a preservative, glycols, and water; the liquid colchicine solution is stable for at least one month at refrigerated and ambient temperature conditions, and the P-gp inhibitor is carvedilol phosphate.
 2. The method of claim 1, wherein the dose of colchicine is 0.5-1.2 mg/dose/day.
 3. The method of claim 1, wherein the dose of carvedilol phosphate is 10-80 mg/dose/day.
 4. The method of claim 3, wherein there is no significant effect on colchicine blood levels when the liquid colchicine solution is taken in conjunction with carvedilol phosphate.
 5. The method of claim 1, wherein the liquid colchicine solution further comprises one or more agents selected from the group consisting of propylene glycol, glycerin, benzyl alcohol, xanthan gum, sucralose, a dye, and a flavoring agent and/or taste enhancing agent.
 6. The method of claim 1, wherein the liquid colchicine solution has a stable pH.
 7. The method of claim 1, wherein the liquid colchicine solution has a viscosity in the range of 40-800 cps.
 8. The method of claim 1, wherein the liquid colchicine solution has less than 5% of total impurities.
 9. The method of claim 1, wherein the liquid colchicine solution has less than 0.5% of degradants.
 10. The method of claim 9, wherein the degradants comprise β-lumicolchicine, γ-lumicolchicine, and/or colchiceine.
 11. The method of claim 1, wherein the liquid colchicine solution is a 0.12 mg/ml solution.
 12. A method of treating gout, comprising orally co-administering a liquid colchicine solution and a P-gp inhibitor to a human subject in an effective amount to treat gout, wherein the liquid colchicine solution comprises a concentration of colchicine of 0.01-1.0 mg/ml, 0.1-0.3% w/v of anhydrous citric acid, 0.8-1.6% w/v of dibasic sodium phosphate heptahydrate, 0.1-0.2% w/v of a thickening agent, a preservative, glycols, and water; the liquid colchicine solution is stable for at least one month at refrigerated and ambient temperature conditions, and the P-gp inhibitor is carvedilol phosphate.
 13. The method of claim 12, wherein the liquid colchicine solution is a 0.12 mg/ml solution. 